This invention relates to a new medicament characterized by the fact that it contains, as the active substance, 5-methoxy psoralen having the formula ##STR1##
It is known that certain furocoumarins, including psoralen and certain of its derivatives, exhibit a photo-dynamic activity which gives rise to photodermatitis. This dermatitis appears after oral or topical administration of the furocoumarins to a mammal and exposure to the sun or to ultra-violet rays.
In the studies which have been carried out on the phototoxicity of psoralen and its derivatives; it has been shown that the most photodynamic or phototoxic composition was psoralen itself having the formula ##STR2## followed, in decreasing order, by 4'-methyl-psoralen, 8-methoxy psoralen, 4,5'-dimethylxanthotoxin, 4-methylxanthotoxin, 5-methoxypsoralen and 5-ethoxy-psoralen. The decrease in the phototoxicity within this group is substantial. The phototoxicity of 8-methoxy-psoralen, is only 37.5% of that of psoralen; the phototoxicity of 5-methoxy-psoralen is only 27.5% of that of psoralen.
It has been found that the therapeutic activity of the psoralens is directly proportional to their phototoxicity. It has also been found that 8-methoxy-psoralen is useful in the treatment of psoriasis. This treatment is known and is generally carried out in the following fashion: 8-methoxy-psoralen is administered orally followed several hours later by irradiation with ultraviolet A rays of large wavelength (360 nanometers) and high intensity. This treatment is carried out twice a week and the maximum dose of 8-methoxy-psoralen administered is on the order of 50 mmg. The results obtained are good in that an extensive "bleaching" of the psoriasis is obtained. The secondary effects observed are the appearance of erythemas, nausea, pruritis, and headache, which result from the toxicity of the product and the intense irradiation.
In accordance with the present invention it has been discovered that, contrary to what might have been believed, another derivative of psoralen which is less phototoxic than 8-methoxy-psoralen and, therefore, less therapeutically active, displays a number of completely unexpected properties which make it much more suitable for therapeutic use and in particular more effective in the treatment of psoriasis.
This derivative is 5-methoxy-psoralen. It can be extracted from natural or synthetic bergamot oil by the method of preparation disclosed below.
The phototoxicity of 5-methoxy-psoralen is less than that of 8-methoxy-psoralen by about 20-30%. This has been confirmed by comparative clinical studies which have been carried out and involved the oral administration of 40 mmg doses of the two compounds.
5-methoxy-psoralen has also been found much less phototoxic than 8-methoxy-psoralen when administered locally at a concentration of more than 100 ppm.
The present invention also relates to a new synthesis of 5-methoxy-psoralen of the formula: ##STR3## starting from phloroglucinol of the formula: ##STR4## In this synthesis the phloroglucinol is methylated to obtain phloroglucinol mono-methyl ether, which is in turn cyclicized to obtain 6-hydroxy-4-methoxy-3-coumaranone; the coumaranone is reduced in one step to obtain 6-hydroxy-4-methoxy coumaran; the coumaran is then cyclicized to obtain 3,4,4',5'-tetrahydro-5 methoxy psoralen; and that product is hydrogenated to yield 5-methoxy-psoralen.
Other syntheses for psoralen derivatives are also known. For example, TETRAHEDRON LETTERS No. 59 1969, Pergamon Press, Great Britain, pp. 5223-24 discloses syntheses of xanthotoxol and xanthotoxin, having the formulas: ##STR5## respectively. Of these, xanthotoxin has skin photosensitizing activity, whereas xanthotoxol is practically inactive. Neither of these compounds are recognized as being useful therapeutic agents.
The method of synthesizing 5-methoxy-psoralen in accordance with the present invention is of particular interest since the starting material is inexpensive, the synthesis is carried out in fewer steps than the known syntheses of other psoralen derivatives, an inexpensive catalyst may be used for the reduction of the coumaranone which is free of the drawbacks of aging and regeneration inherent in other catalysts, and it gives good yields. It is an object of the present invention to provide a new pharmaceutical formulation comprising 5-methoxy-psoralen.
A further object of the present invention is to provide a method of treating psoriasis and other skin conditions by administration of pharmaceutical formulations which contain 5-methoxy-psoralen.
A still further object of the present invention is to provide a new process of synthesizing 5-methoxy-psoralen.
These and other objects of the present invention will be understood in conjunction with the following detailed specification.